This grant application seeks to define the genetic and neural circuit basis of the functional role of the ventromedial hypothalamus (VMH). The VMH is molecularly heterogeneous and correspondingly, it has been implicated in the regulation of diverse behaviors and physiological function: motor and visceromotor functions, neuroendocrine function, feeding, and sexually dimorphic social and emotional behaviors. One appealing possibility is that these diverse functions are controlled by discrete subsets of VMH neurons. We and others have identified a small cluster of sexually dimorphic neurons within the VMH. We hypothesize that these neurons control sexually dimorphic social and emotional behaviors. In Aim 1, we will use a novel Cre recombinase mouse strain we have generated to genetically trace the connections of these dimorphic VMH neurons. We will also test the hypothesis that projections to different areas emanating from these dimorphic neurons are activated during distinct behaviors. In Aim 2, we will utilize a novel Cre-dependent, pro-apoptotic gene to genetically ablate these dimorphic VMH neurons in adult males and females. These mice will subsequently be tested for deficits in dimorphic social and emotional behaviors. In Aim 3, we will utilize a Cre- dependent heterologous receptor (DREADD) activated by a heterologous ligand (clozapine-N-oxide) to switch on activity in these VMH neurons in vivo in males and females. This experiment will test whether activity in these neurons is sufficient to elicit dimorphic socia and emotional behavior. Taken together, our molecular genetic approaches will uncover the connectivity and functional relevance of a sexually dimorphic neuronal cluster in the mammalian forebrain. Health Relatedness: The devastating clinical manifestations of common neurodegenerative conditions and psychiatric conditions often reflect dysfunction of specific neural circuits. The VMH has been implicated in the regulation of social and emotional behaviors, neuroendocrine function, feeding, and motor and visceromotor function. VMH-localized lesions such as tumors result in altered cognition, abnormal social behaviors, and metabolic changes. Our studies will provide novel mechanistic insight into the functional relevance of the VMH and the circuits in which it participates in health. These findings may ultimately allow development of more rationally-targeted diagnostic and therapeutic options for VMH dysfunction in neurological disorders. Finally, the Cre-dependent, pro-apoptotic genetically encoded reagent that we use in this proposal will be useful in developing models of neurodegeneration in any neuronal (or other cell) type.